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Background Psoriasis vulgaris is the most common form of psoriasis, yet current treatments often lead to significant side effects, resulting in a high rate of therapy desertion. Here, we explored a novel therapeutic approach using the secretome from Wharton Jelly-derived mesenchymal stem cells, biologically stabilized and enhanced with hyaluronic acid (HA), its presentation is an easy-to-apply topical sponge. This formulation had previously demonstrated efficacy in vitro and in experimental psoriasis mouse models. Methods In vitro characterization studies included dynamic light scattering, nanoparticle tracking analysis, optical/electronic microscopy, microbiological experiments, and angiogenic capacity (HUVEC cells). In vivo studies included angiogenic capacity in chicken embryo chorioallantoic membrane (CAM), safety (hypersensitive and healthy volunteers), and efficacy (double-blinded and randomized patients). Results We demonstrated the presence of spherical exosomes (164 ± 87 nm, PDI of 0.38, and 1.5 × 10⁷ particles/mL) within the selected secretomes, which exhibited significant proangiogenic activity in HUVEC cells and in a CAM assay. The secretome-containing sponges displayed distinct physicochemical properties, such as the absence of nitrogen and reduced carbon and oxygen content, resulting in a more cross-linked material with thinner fibers. These characteristics extended the dispersion time in aqueous media. Microbiological testing confirmed sterility in the packed, ready-to-use secretome-HA sponges after 3 months of storage. To assess safety, we selected doses (based on total protein content) that were applied to three patients with atopic dermatitis (42 µg of protein, patch test, 5 days) and four healthy volunteers (210 µg, 15 days) with no observed adverse topical or systemic effects. In a 30-day efficacy study, 12 patients with bilateral psoriasis exhibited up to a 33% reduction in mPASI scores and a 41% decrease in plaque size. Additionally, transepidermal water loss (TEWL) was reduced by up to 30%, while skin elasticity/flexibility improved by 43%. Conclusions These findings suggest that the topical application of the secretome-HA sponge is a safe and effective therapeutic option for alleviating symptoms of psoriasis vulgaris . Trial registration SSMN, SSMN047/2021. Registered 27 October 2021, https://www.ssmn.cl/comite_etica.php . Graphical abstract

Mesenchymal stem/stromal cells (MSCs) are widely described in the context of their regenerative and immunomodulatory activity. MSCs are isolated from various tissues and organs. The most frequently described sources are bone marrow and adipose tissue. As stem cells, MSCs are able to differentiate into other cell lineages, but they are usually reported with respect to their paracrine potential. In this review, we focus on MSCs derived from adipose tissue (AT-MSCs) and their secretome in regeneration processes. Special attention is given to the contribution of AT-MSCs and their derivatives to angiogenic processes described mainly in the context of angiogenic dysfunction. Finally, we present clinical trials registered to date that concern the application of AT-MSCs and their secretome in various medical conditions.

Pyroptosis is a lytic cell death mode that helps limit the spread of infections and is also linked to pathology in sterile inflammatory diseases and autoimmune diseases 1 – 4 . During pyroptosis, inflammasome activation and the engagement of caspase-1 lead to cell death, along with the maturation and secretion of the inflammatory cytokine interleukin-1β (IL-1β). The dominant effect of IL-1β in promoting tissue inflammation has clouded the potential influence of other factors released from pyroptotic cells. Here, using a system in which macrophages are induced to undergo pyroptosis without IL-1β or IL-1α release (denoted Pyro −1 ), we identify unexpected beneficial effects of the Pyro −1 secretome. First, we noted that the Pyro −1 supernatants upregulated gene signatures linked to migration, cellular proliferation and wound healing. Consistent with this gene signature, Pyro −1 supernatants boosted migration of primary fibroblasts and macrophages, and promoted faster wound closure in vitro and improved tissue repair in vivo. In mechanistic studies, lipidomics and metabolomics of the Pyro −1 supernatants identified the presence of both oxylipins and metabolites, linking them to pro-wound-healing effects. Focusing specifically on the oxylipin prostaglandin E 2 (PGE 2 ), we find that its synthesis is induced de novo during pyroptosis, downstream of caspase-1 activation and cyclooxygenase-2 activity; further, PGE 2 synthesis occurs late in pyroptosis, with its release dependent on gasdermin D pores opened during pyroptosis. As for the pyroptotic metabolites, they link to immune cell infiltration into the wounds, and polarization to CD301 + macrophages. Collectively, these data advance the concept that the pyroptotic secretome possesses oxylipins and metabolites with tissue repair properties that may be harnessed therapeutically. Defining the composition of the secretome of pyroptotic macrophages reveals the involvement of the component factors in wound healing.

As spaceflight becomes more common with commercial crews, blood-based measures of crew health can guide both astronaut biomedicine and countermeasures. By profiling plasma proteins, metabolites, and extracellular vesicles/particles (EVPs) from the SpaceX Inspiration4 crew, we generated “spaceflight secretome profiles,” which showed significant differences in coagulation, oxidative stress, and brain-enriched proteins. While >93% of differentially abundant proteins (DAPs) in vesicles and metabolites recovered within six months, the majority (73%) of plasma DAPs were still perturbed post-flight. Moreover, these proteomic alterations correlated better with peripheral blood mononuclear cells than whole blood, suggesting that immune cells contribute more DAPs than erythrocytes. Finally, to discern possible mechanisms leading to brain-enriched protein detection and blood-brain barrier (BBB) disruption, we examined protein changes in dissected brains of spaceflight mice, which showed increases in PECAM-1, a marker of BBB integrity. These data highlight how even short-duration spaceflight can disrupt human and murine physiology and identify spaceflight biomarkers that can guide countermeasure development. Here the authors report spaceflight secretome profiles by integrating plasma proteome, metabolome, and extracellular vesicles/particles proteome from the SpaceX Inspiration4 crew, which showed differences in coagulation, oxidative stress, and brain-enriched proteins.

The long-held belief about adipose tissue was that it was relatively inert in terms of biological activity. It was believed that its primary role was energy storage; however, that was shattered with the discovery of adipokines. Scientists interested in regenerative medicine then reported that adipose tissue is rich in adult stromal/stem cells. Following these initial reports, adipose stem cells (ASCs) rapidly garnered interest for use as potential cellular therapies. The primary advantages of ASCs compared to other mesenchymal stem cells (MSCs) include the abundance of the tissue source for isolation, the ease of methodologies for tissue collection and cell isolation, and their therapeutic potential. Studies conducted both in vitro and in vivo have demonstrated that ASCs are multipotent, possessing the ability to differentiate into cells of mesodermal origins, including adipocytes, chondrocytes, osteoblast and others. Moreover, ASCs produce a broad array of cytokines, growth factors, nucleic acids (miRNAs), and other macromolecules into the surrounding milieu by secretion or in the context of microvesicles. The secretome of ASCs has been shown to alter tissue biology, stimulate tissue-resident stem cells, change immune cell activity, and mediate therapeutic outcomes. The quality of ASCs is subject to donor-to-donor variation driven by age, body mass index, disease status and possibly gender and ethnicity. This review discusses adipose stromal/stem cell action mechanisms and their potential utility as cellular therapeutics.

Although culturing cells in serum‐free or low‐serum media may lead to reduced cell proliferation, it is crucial to minimise the presence of foreign proteins and other impurities that could compromise the validity of experimental findings on immunomodulation. The study aimed to investigate the immunomodulatory effects of the secretome derived from the serum‐free media (SFM) of stem cells obtained from human exfoliated deciduous teeth on THP‐1‐derived macrophage polarisation and the assessment of inflammatory and oxidative stress mediators. THP‐1 cells were polarised into M0 and M1 macrophages, and their differentiation was confirmed using flow cytometry to analyse specific markers of M0 (CD14 and CD68) and M1 (CD80 and CD86). The secretome was collected from SHED‐MSCs cultured for 48 h in serum‐free DMEM/F12 media. After treating THP‐1‐derived M0/M1 macrophages with SFM‐secretome from SHED‐MSCs, cells and supernatants were evaluated for immunosuppressive (anti‐inflammatory and antioxidant) and immunostimulatory (pro‐inflammatory and pro‐oxidant) indicators. Secretome treatment decreased the population of M1 macrophages, along with the expression of pro‐inflammatory and pro‐oxidative markers, including CD80, CD86, TNF‐α, IL‐12, NO, MDA and IL‐6R. The immunomodulatory effect of the secretome produced by SFM, which may help reduce inflammation, is demonstrated by an increase in M2 macrophages and anti‐inflammatory and antioxidant markers, including CD206, TGFβ‐2, IL‐10, TAC, CAT, SOD and ARG1. The secretome produced by SFM‐derived SHED‐MSCs may reduce the risk of introducing foreign proteins and other potentially hazardous chemicals and enhance the efficacy of cellular secretions for applications such as immunotherapy or regenerative medicine by modulating the immune system.

Mesenchymal stem cells (MSCs) are known for their beneficial effects and regenerative potential. In particular, dental-derived MSCs have the advantage of easier accessibility and a non-invasive isolation method. Moreover, thanks to their neural crest origin, dental MSCs seem to have a more prominent neuroregenerative potential. Indeed, in basal conditions they also express neuronal markers. However, it is now well known that the beneficial actions of MSCs depend, at least in part, on their secretome, referring to all the bioactive molecules released in the conditioned medium (CM) or in extracellular vesicles (EVs). In this review we focus on the applications of the secretome derived from dental MSCs for neuroregeneration and neuroprotection. The secretomes of different dental MSCs have been tested for their effects for neuroregenerative purposes, and the secretomes of dental pulp stem cells and stem cells from human exfoliated deciduous teeth are the most studied. Both the CM and EVs obtained from dental MSCs showed that they are able to promote neurite outgrowth and neuroprotective effects. Interestingly, dental-derived MSC secretome showed stronger neuroregenerative and neuroprotective effects compared to that obtained from other MSC sources. For these reasons, the secretome obtained from dental MSCs may represent a promising approach for neuroprotective treatments.

Mesenchymal stromal cells isolated from menstrual blood (MenSCs) exhibit a potent pro-angiogenic and immunomodulatory capacity. Their therapeutic effect is mediated by paracrine mediators released by their secretomes. In this work, we aimed to evaluate the effect of a specific priming condition on the phenotype and secretome content of MenSCs. Our results revealed that the optimal condition for priming MenSCs was the combination of interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα) that produced a synergistic and additive effect on IDO1 release and immune-related molecule expression. The analyses of MenSC-derived secretomes after IFNγ and TNFα priming also revealed an increase in EV release and in the differentially expressed miRNAs involved in the immune response and inflammation. Proliferation assays on lymphocyte subsets demonstrated a decrease in CD4+ T cells and CD8+ T cells co-cultured with secretomes, especially in the lymphocytes co-cultured with secretomes from primed cells. Additionally, the expression of immune checkpoints (PD-1 and CTLA-4) was increased in the CD4+ T cells co-cultured with MenSC-derived secretomes. These findings demonstrate that the combination of IFNγ and TNFα represents an excellent priming strategy to enhance the immunomodulatory capacity of MenSCs. Moreover, the secretome derived from primed MenSCs may be postulated as a therapeutic option for the regulation of adverse inflammatory reactions.

The widespread use of multipotent mesenchymal stromal cell-derived secretome (MSC-sec) requires optimal preservation methods. Lyophilization offers benefits like concentrating the secretome, reducing the storage volume, and making storage conditions more flexible. This study evaluated the influence of storage duration and temperature on lyophilized MSC-sec. The conditioned medium from Wharton’s jelly MSCs was stored at – 80 °C or lyophilized with or without trehalose. Lyophilized formulations were kept at – 80 °C, − 20 °C, 4 °C, or room temperature (RT) for 3 and 30 months. After storage and reconstitution, the levels of growth factors and cytokines were assessed using multiplex assay. The storage of lyophilized MSC-sec at – 80 °C ensured biomolecule preservation for 3 and 30 months. Following 3 month storage at 4 °C and RT, a notable decrease occurred in BDNF, bNGF, and sVCAM-1 levels. Prolonged 30 month storage at the same temperatures significantly reduced BDNF, bNGF, VEGF-A, IL-6, and sVCAM-1, while storage at – 20 °C decreased BDNF, bNGF, and VEGF- A levels. Trehalose supplementation of MSC-sec improved the outcome during storage at 4 °C and RT. Proper storage conditions were crucial for the preservation of lyophilized MSC-sec composition. Short-term storage at various temperatures maintained over 60% of the studied growth factors and cytokines; long-term preservation was only adequate at −80 °C.

Skeletal musculature represents the largest organ in the human body, playing a vital role in systemic metabolism, physiological functions, and glucose homeostasis. Skeletal muscles are also a significant source of multiple humoral factors, including myokines, which are, as part of the muscular secretome, involved in cellular signaling within and outside of the muscle. Myokines are a group of cytokines that exert a major influence on muscle metabolism through autocrine mechanisms and are involved in para- or endocrine regulation in organs outside of muscle tissue, such as the pancreas, adipose tissue, liver, heart, bone, gastrointestinal tract, and brain. In the future, these findings could be crucial for the identification of important biomarkers used for the monitoring of physical activity in the treatment of pathologies such as intensive care-associated muscle wasting, sarcopenia, diabetes, neurodegenerative diseases, etc. As skeletal muscle tissue is intrinsically linked to multiple types of tissues and organs metabolically, functionally, and most importantly, regionally, there can be a significant overlap between the auto- and paracrine effects of myokines, depending on the presence of that myokine. The following section will discuss the auto-, para-, and endocrine effects of some of the myo-inducible cytokines on skeletal muscles and adjacent tissue types.